Investigation of IRE1/XBP1s pathway and its potential as a therapeutic target in breast cancer

View/Open

Date

Author

Metadata

Usage

Abstract

X-Box binding protein 1 (XBP1) is an integral component of the unfolded protein response
(UPR), a pro-survival mechanism, triggered by the onset of endoplasmic reticulum stress.
Activation of the endoplasmic reticulum localized stress sensor IRE1α removes a 26
nucleotide intron from XBP1 mRNA generating the active transcription factor XBP1
spliced (XBP1s). Signalling via this arm of the UPR is generally thought to be pro-survival
and represents a mechanism through which cells can endure stressful conditions. High
levels of XBP1s are linked to breast cancer, with overexpression reported across a range of
subtypes where it correlated with a worse patient outcome. In this study routinely used
breast cancer cell lines (MCF-7, T47D, SKBR3, MDA-MB231) were found to have basal
protein expression of XBP1s. To determine the relevance of basal XBP1s levels a novel
chemical inhibitor of IRE1 was employed which specifically inhibits IRE1 ribonuclease
activity and therefore block XBP1 splicing. Addition of the IRE1 inhibitor efficiently
reduced basal levels of XBP1s in all cell lines tested. Prolonged treatment with the IRE1
inhibitor significantly reduced cell proliferation in breast cancer cells and induced cell death
under reduced serum conditions. Interesting, cell death was found to be mediated through
modulation of extracellular factors. Moreover, screening of commonly used anti-cancer
drugs revealed that IRE1 inhibition could enhance the cytotoxicity of commonly used anticancer
drugs. In parallel to this study a novel downstream target of IRE1/XBP1s was
identified; Sestrin 2. Sestrin 2 knockdown highlighted the pro-survival effects of Sestrin 2
during treatment of breast cancer cells with Methotrexate and Bortezomib, presenting a new
therapeutic target in breast cancer treatment.
In summary, this thesis investigates the role of IRE1/XBP1s signalling in breast cancer and
demonstrates the clinical potential of IRE1 inhibition.

URI

Collections

This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. Please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.